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Chronic Sinusitis:Update

Larry Borish, M.D.Professor of Medicine and Microbiology

University of Virginia Health SystemsCharlottesville, VA

Conflicts of Interest

• Grant Support: NIH*, GSK*, Astra Zeneca*

• Consulting: Astra Zeneca, Sanofi-Regeneron

• Clinical Trial: Cumberland*

*All funds go to UVA

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Learning Objectives• To appreciate distinct CRS phenotypes

but limitations in their diagnosis

• To appreciate the potential role ofspecific individualized biologics inCRS

Phenotypes of CRS

• Non-eosinophilic• Th1 / Th17 / innate

• ± Neutrophilic

• CF (often)

• Eosinophilic• Idiopathic

• AERD

• AFS

• CF (often)

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Non-Eosinophilic CRS

100x200xPayne, SP et al. Laryngoscope 2011;121:2262-7

Clinical Aspects ofNon-Eosinophilic CRS

• Inflammatory sinonasal disease

- e.g., perennial allergic / non-allergic rhinitis

• Frequent episodes of bacterial sinusitis

• Less often associated with nasal polyposis

• No asthma or eosinophilia?

• 1 FESS may be curative?

• Mucus inclusion cysts on CT / CT scores <12?

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Pathogenesis of Non-Eosinophilic CRS?

Frequent protracted episodes of acute sinusitis

Remodeling of Sinus Tissue

- Epithelial denudation

- Goblet cell and glandular hypertrophy- Fibrosis ± polyp formation

Bacterial colonization- Formation of biofilm

- Chronic purulent exudate

Eosinophilic CRS

200x 100x

Payne, SP et al. Laryngoscope 2011;121:2262-7

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But how useful is this in real life?

• Are these – in fact – distinct phenotypes?

• Can presence or absence of eosinophils (±IL-5 / ± ECP) beused to distinguish type 2/eosinophilic from non-type 2 disease?

• and, can• presence /absence of NPs,• asthma,• absolute eosinophil count,• whatever

• but especially NPs be used as prima facie evidence foreosinophilic disease?

Patterns of Cytokine Expression in CRSsNPsBenelux: Chengdu:

Wang X et al. J Allergy Clin Immunol 2016;138:1344-53

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Patterns of Cytokine Expression in CRSwNPsBenelux: Chengdu:

Tomassen P et al. J Allergy Clin Immunol 2016;137:1449-56

Presence of eosinophilia (ECP) / IL-5 in CRSwand CRSs NPs

Tomassen P et al. J Allergy Clin Immunol 2016;137:1449-56

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Northwestern’s Experience:

mRNA as % of house keeping gene for CLC and IL-5ECP protein via EIA

ET – ethmoid tissue

Tan BK et al. J Allergy Clin Immunol 2017;139:699

But how useful is this in real life (part 2)?

• Are these – in fact – distinct phenotypes?

• Can presence or absence of eosinophils (±IL-5 / ± ECP) be used todistinguish type 2/eosinophilic from non-type 2 disease?

- is someone with 1189.10 µg/L of ECP in their polyp tissue really“eosinophilic” whereas someone with 1189.09 µg of ECP is non-eosinophilic?

• Can clinical criteria distinguish type 2 high NPs?

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Do biomarkers predict tissue eosinophilia?

Tissue Average Eosinophilia Tertile

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ea

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1st 2nd 3rd

200

400

600

800

1000

Tissue Average Eosinophilia Tertile

Ge

om

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ea

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1st 2nd 3rd

0

100

200

300

400

Tissue Average Eosinophilia Tertile

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1st 2nd 3rd

10

12

14

16

18

20

A B

C

p = 0.205

p = 0.149

p = 0.311

Steinke J et al. J Allergy Clin Immunol: Practice 2017;5(6):1582-8

and, for the matter, how well does tissueeosinophilia predict “eosinophilia”?

Average Tissue Eosinophil Count Interval

Fre

qu

en

cy

(n)

0

5

10

15

20

25

30

Fre

qu

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cy

(n)

0

5

10

15

20

25

30

[0-3)[3-5)

[5-7)[7-9)

[9-11)[11-13)

[13-15)

[15-17)

[17-19)

[19-21)

[21-23)

[23-25)

[25, + )

Peak Tissue Eosinophil Count Interval

A

B

[0-3)[3-5)

[5-7)[7-9)

[9-11)[11-13)

[13-15)

[15-17)

[17-19)

[19-21)

[21-23)

[23-25)

[25, + )

and, does it make adifference if theeosinophils arediffusely expressedor just present infoci?

Steinke J et al. J Allergy Clin Immunol: Practice 2017;5(6):1582-8

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So if these are (primarily) eosinophilic diseasesshouldn’t eosinophil depletion cure them?

e.g.,- IL-5 antagonists- dexpramipexole

Biological Activities of IL-5

• IL-5 is the most important eosinophil hematopoietin• TSLP and IL-33 may also have a role in the induction of inducible

eosinophilia

• also, eosinophils are constitutively made

• IL-5 is an important survival factor for eosinophils• although in the airway autocrine production of GM-CSF may take on a more

important role

• IL-5 is chemotactic for mature eosinophils and a priming factor forenhanced functional activities

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Anti-IL-5 / Anti-IL-5R

• Anti-IL-5 will deplete bone marrow and circulating eosinophils- although less effective in depleting tissue eosinophils (~50%)

- Anti-IL-5R will block IL-5 engagement on IL-5R on eosinophils- but via ADCC may opsonize and deplete eosinophils in the absence of IL-5

- and may target other IL-5R+ cells (e.g., basophils)

Anti-IL-5 in CRS

Gevaert, P et al. J Allergy Clin Immunol 2011;128:989-995

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Bachert C. et al. J Allergy Clin Immunol 2017;140:1024-31

Mepolizumab reduces need for surgery

Who might respond best to eosinophiltargeting therapies?

• Presumably those with an eosinophil-mediated disease

- IL-5high

- other specific phenotypes? e.g.,• AERD• EGPA

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Nasal IL-5 levels determine the responseto anti-IL-5 in nasal polyposis:

• DBPC randomized trial ofreslizumab in NPs

• Reslizumab reduced AECand serum ECP for up to8 weeks

• NP response lasted for 4weeks

Gevaert, P et al. J Allergy Clin Immunol 2006;118:1133-41

Problems with eosinophil targeting therapies

• We have no meaningful markers as to who has eosinophilic disease- AEC, NPs, FeNO, and perhaps even tissue biopsies are all inadequate

• Current therapies may not adequately eliminate tissue eosinophils

• Even if tissue eosinophils were all eradicated, CRSs or wNPs mayvariably be driven by numerous other inflammatory cells:

- Basophils

- Mast cells

- PMNs

- others

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So, is eosinophil elimination sufficient toeradicate CRSwNPs?

Eosinophil Reduction in NPs: Dexpramipexole

Laidlaw, TM et al. Laryngoscope doi.org/10.1002/lary.27564

Tissue histology:

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and how does that translate in terms ofclinical benefit?

Laidlaw, TM et al. Laryngoscope doi.org/10.1002/lary.27564

So if this isn’t (just) an eosinophilic diseasewhat else might it be?• What is the role of mast cells in refractory CRSwNPs?

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CHLOROACETATEANTIBODY

Payne, SP et al. Laryngoscope 2011;121:2262-7

and, a fun bonus observation in thedexpramipexole study:

Laidlaw, TM et al. Laryngoscope doi.org/10.1002/lary.27564

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How might mast cells be activated in CRS?

• IgE- aeroallergen (perhaps)

- staph (intriguing)

- something local?

• Non-IgE- cytokines: IL-4/IL-13, TSLP/IL-25/IL-33, numerous chemokines/cytokines

- LTE4

- TNTC alarmins / PAMPs

Can Allergen Even Access the Sinuses?

• Radiolabeled allergen can not access the sinus cavityAdkins, T.N. et al. Ann Allergy Asthma Immunol. 1998;81:181-4

• Radioisotope placed on nasal mucosa can access the healthy sinuscavity with nose blowing but not with nasal breathing, sneezing, orcoughing

Gwaltney JM Jr., et al. Clin Infect Dis 2000;30:387-9

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CRS exacerbations occur in a seasonal pattern

Rank MA, J Allergy Clin Immunol 126:168, 2010but that seasonal pattern is the season of respiratory viral infections!

Which argues against CRS being an “allergic”disease

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Does efficacy of omalizumab support an“allergic” mechanism for CRS?

Efficacy of omalizumab in non-atopic asthma* andchronic urticaria

*deLlano, LP et al. J. Asthma 2013;50(3):296-301

and, in the CRS study (pending)…

improvements occurred irrespective of thepresence of allergy

IgE in Chronic Sinusitis:Mucosal tissue polyclonal IgE is functional but not particularlyresponsive to allergen

Zhang N et al Allergy 2011;66:141-8

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IgE in Chronic Sinusitis:Mucosal tissue polyclonal IgE is functional but not particularlyresponsive to allergen

Zhang N et al Allergy 2011;66:141-8

Non-IgE Mechanisms?

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Implications for Treatment

• IgE targeting therapies• Omalizumab

• Mast cell stabilizers / mast cell targeting therapeutics• Omalizumab

• Dupilumab

• Imatinib?

• Anti-SigLEC8?

Omalizumab in CS

• Improvements occurred irrespective of presence of allergy• Omalizumab may be particularly effective in AERD

Gevaert P et al. 2013 J Allergy Clin Immunol 131:110-6Bergmann KC et al. 2015 J Allergy Clin Immunol Pract 3:459-60)

• 16 week DBPC study of omalizumab in 24 (16:8) subjectswith asthma and NPs

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Dupilumab in CRS: IL-4 and IL-13Receptors

Unique patterns of distribution of type I (IL-4)and type II (IL-4 and IL-13) receptors

IL-4 (g chainexpression)

Hematopoieticcells

T lymphocytesmast cells

IL-13 (type IIreceptors)

Hematopoieticand non-hematopoieticcells

Epithelial cells,smooth muscle,endothelialcells

IL-4 and “Leaky” Mast Cells: IL-4 InducesExpression of FcRI on Mast Cells

Pawankar R, et al. J Clin Invest 1997;99:1492

IL-4 but not IL-13 inducesFceRI on human mast cells

IL-4-stimulated mast cells (lane 1)demonstrate enhanced expressionof FceRIa chain

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IL-4 Regulates IgE-dependent CysLT production by MastCells: Profound Induction of LTC4 Synthase expression byIL-4:

Hsieh FH et al. J. Exp Med. 2001;193:123.

Effect of IL-4 priming of human MCs onIgE mediated CysLT release

Effect of IL-4 priming on5-LO/LTC4S pathwayprotein expression byhMCs

Distal actions of IL-13 inallergic inflammation

• Endothelial cells: Eosinophil adhesion;chemokine expression

• Airway smooth muscle hyperplasia: Bronchialhyperreactivity

• Epithelial cell metaplasia

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IL-13 and Goblet Cell Metaplasia

• IL-13 induces reversible trans-differentiation ofepithelial cells into goblet cells

• This occurs via expression of foxa3 (master regulatorof goblet cells)– which drive expression of mucin genes (Muc5ac)

Effect of IL-13 on Mucus Production

AB/PAS(mucus stain

MUC5AC geneexpression

Control

IL-13(250 ng i.n.,single dose)

Dabbagh K, et al. J Immunol 1999; 162:6233-7.

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Dupilumab for CRS

Bachert C et al. JAMA 2016;315:469-479

Nasal polyp score:

Dupilumab for CRSSNOT22 Score

Bachert C et al. JAMA 2016;315:469-479

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Dupilumab in AERD

• Clearly can be beneficial…. But in whom?• AERD

Nasal polyp Scores:

Where biologics may be most useful• IL-5/IL-5R antagonists:

• CRS with or without NPs where pathological exam demonstrates robusteosinophilia

• AERD• EGPA (mepolizumab 300 mg/month)

• Omalizumab• atopic rhinosinusitis• ? AFS (no data)

• Dupilumab• ? excessive mucus metaplasia• AERD

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Summary

• Eosinophils alone cannot explain the severity of CRSwNPs- eosinophil depletion is useful but no panacea

• Mast cells are an inviting and underappreciated target in CRS- they are present in high numbers

- they are activated

- and, even if not IgE-mediated, you don’t need IgE to activate a mast cell

• IgE / mast cell targeting therapies show promise